tbuckley/cabot-search huggingface dataset:
Liquid biopsy epigenomic profiling for cancer subtyping
Authors: Sylvan C. Baca, Ji-Heui Seo, Matthew P. Davidsohn, Brad Fortunato, Karl Semaan, Shahabbedin Sotudian, Gitanjali Lakshminarayanan, Miklos Diossy, Xintao Qiu, Talal El Zarif, Hunter Savignano, John Canniff, Ikenna Madueke, Renee Maria Saliby, Ziwei Zhang, Rong Li, Yijia Jiang, Len Taing, Mark Awad, Cindy H. Chau, James A. DeCaprio, William D. Figg, Tim F. Greten, Aaron N. Hata, F. Stephen Hodi, Melissa E. Hughes, Keith L. Ligon, Nancy Lin, Kimmie Ng, Matthew G. Oser, Catherine Meador, Heather A. Parsons, Mark M. Pomerantz, Arun Rajan, Jerome Ritz, Manisha Thakuria, Sara M. Tolaney, Patrick Y. Wen, Henry Long, Jacob E. Berchuck, Zoltan Szallasi, Toni K. Choueiri, Matthew L. Freedman
Journal: Nature Medicine (2023)

Abstract Although circulating tumor DNA (ctDNA) assays are increasingly used to inform clinical decisions in cancer care, they have limited ability to identify the transcriptional programs that govern cancer phenotypes and their dynamic changes during the course of disease. To address these limitations, we developed a method for comprehensive epigenomic profiling of cancer from 1 ml of patient plasma. Using an immunoprecipitation-based approach targeting histone modifications and DNA methylation, we measured 1,268 epigenomic profiles in plasma from 433 individuals with one of 15 cancers. Our assay provided a robust proxy for transcriptional activity, allowing us to infer the expression levels of diagnostic markers and drug targets, measure the activity of therapeutically targetable transcription factors and detect epigenetic mechanisms of resistance. This proof-of-concept study in advanced cancers shows how plasma epigenomic profiling has the potential to unlock clinically actionable information that is currently accessible only via direct tissue sampling.
Skin Investigation Network of Canada (SkIN Canada) Priority Setting Initiative ranks the top 10 evidence uncertainties for Merkel cell carcinoma
Authors: Anabel Bergeron, Carolyn Nessim, Omer Kleiner, Rachael Manion, Jan Dutz, Anie Philip, An-Wen Chan, Yuka Asai, Kathleen Barnard, John Beaty, Leslee Beaty, Beverly Bell-Rowbotham, Ryan DeCoste, Aaron M Drucker, Julie Fradette, Lucie Germain, Robert Gniadecki, Karen Holfeld, Yuanshen Huang, Melanie Laurin, Ivan V Litvinov, Sarvesh Logsetty, Trish MacNeil, Morris F Manolson, Roxana Mititelu, P Régine Mydlarski, Vincent Piguet, Girish Shah, Debbie Ward, Mary Zawadaski, Youwen Zhou
Journal: British Journal of Dermatology (2023)

The Skin Investigation Network of Canada (SkIN Canada) completed a national Priority Setting Initiative to identify the top 10 knowledge uncertainties for Merkel cell carcinoma based on the James Lind Alliance principles. Overall, 48 patients, clinicians and researchers provided input in two survey rounds and one workshop. The top 10 list of research priorities will help the skin research community, funders and policymakers to address key knowledge uncertainties for the benefit of patients with Merkel cell carcinoma.
Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma
Authors: Yohann Loriot, Nobuaki Matsubara, Se Hoon Park, Robert A. Huddart, Earle F. Burgess, Nadine Houede, Severine Banek, Valentina Guadalupi, Ja Hyeon Ku, Begoña P. Valderrama, Ben Tran, Spyros Triantos, Yin Kean, Sydney Akapame, Kris Deprince, Sutapa Mukhopadhyay, Nicole L. Stone, Arlene O. Siefker-Radtke
Journal: New England Journal of Medicine (2023)

Erdafitinib is a pan-fibroblast growth factor receptor (FGFR) inhibitor approved for the treatment of locally advanced or metastatic urothelial carcinoma in adults with susceptible FGFR3/2 alterations who have progression after platinum-containing chemotherapy. The effects of erdafitinib in patients with FGFR-altered metastatic urothelial carcinoma who have progression during or after treatment with checkpoint inhibitors (anti-programmed cell death protein 1 [PD-1] or anti-programmed death ligand 1 [PD-L1] agents) are unclear. We conducted a global phase 3 trial of erdafitinib as compared with chemotherapy in patients with metastatic urothelial carcinoma with susceptible FGFR3/2 alterations who had progression after one or two previous treatments that included an anti-PD-1 or anti-PD-L1. Patients were randomly assigned in a 1:1 ratio to receive erdafitinib or the investigator's choice of chemotherapy (docetaxel or vinflunine). The primary end point was overall survival. A total of 266 patients underwent randomization: 136 to the erdafitinib group and 130 to the chemotherapy group. The median follow-up was 15.9 months. The median overall survival was significantly longer with erdafitinib than with chemotherapy (12.1 months vs. 7.8 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.47 to 0.88; P = 0.005). The median progression-free survival was also longer with erdafitinib than with chemotherapy (5.6 months vs. 2.7 months; hazard ratio for progression or death, 0.58; 95% CI, 0.44 to 0.78; P<0.001). The incidence of grade 3 or 4 treatment-related adverse events was similar in the two groups (45.9% in the erdafitinib group and 46.4% in the chemotherapy group). Treatment-related adverse events that led to death were less common with erdafitinib than with chemotherapy (in 0.7% vs. 5.4% of patients). Erdafitinib therapy resulted in significantly longer overall survival than chemotherapy among patients with metastatic urothelial carcinoma and FGFR alterations after previous anti-PD-1 or anti-PD-L1 treatment. (Funded by Janssen Research and Development; THOR ClinicalTrials.gov number, NCT03390504.).
The Double Antibody Drug Conjugate (DAD) phase I trial: sacituzumab govitecan plus enfortumab vedotin for metastatic urothelial carcinoma
Authors: B.A. McGregor, G.P. Sonpavde, L. Kwak, M.M. Regan, X. Gao, H. Hvidsten, C.M. Mantia, X.X. Wei, J.E. Berchuck, S.A. Berg, P.K. Ravi, M.D. Michaelson, T.K. Choueiri, J. Bellmunt
Journal: Annals of Oncology (2023)
CRISPR/Cas9 systems: Delivery technologies and biomedical applications
Authors: Yimin Du, Yanfei Liu, Jiaxin Hu, Xingxing Peng, Zhenbao Liu
Journal: Asian Journal of Pharmaceutical Sciences (2023)

The emergence of the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) genome-editing system has brought about a significant revolution in the realm of managing human diseases, establishing animal models, and so on. To fully harness the potential of this potent gene-editing tool, ensuring efficient and secure delivery to the target site is paramount. Consequently, developing effective delivery methods for the CRISPR/Cas9 system has become a critical area of research. In this review, we present a comprehensive outline of delivery strategies and discuss their biomedical applications in the CRISPR/Cas9 system. We also provide an in-depth analysis of physical, viral vector, and non-viral vector delivery strategies, including plasmid-, mRNA- and protein-based approach. In addition, we illustrate the biomedical applications of the CRISPR/Cas9 system. This review highlights the key factors affecting the delivery process and the current challenges facing the CRISPR/Cas9 system, while also delineating future directions and prospects that could inspire innovative delivery strategies. This review aims to provide new insights and ideas for advancing CRISPR/Cas9-based delivery strategies and to facilitate breakthroughs in biomedical research and therapeutic applications.
Multidimensional autophagy nano-regulator boosts Alzheimer's disease treatment by improving both extra/intraneuronal homeostasis
Authors: Yixian Li, Peng Yang, Ran Meng, Shuting Xu, Lingling Zhou, Kang Qian, Pengzhen Wang, Yunlong Cheng, Dongyu Sheng, Minjun Xu, Tianying Wang, Jing Wu, Jinxu Cao, Qizhi Zhang
Journal: Acta Pharmaceutica Sinica B (2023)

Intraneuronal dysproteostasis and extraneuronal microenvironmental abnormalities in Alzheimer's disease (AD) collectively culminate in neuronal deterioration. In the context of AD, autophagy dysfunction, a multi-link obstacle involving autophagy downregulation and lysosome defects in neurons/microglia is highly implicated in intra/extraneuronal pathological processes. Therefore, multidimensional autophagy regulation strategies co-manipulating "autophagy induction" and "lysosome degradation" in dual targets (neuron and microglia) are more reliable for AD treatment. Accordingly, we designed an RP-1 peptide-modified reactive oxygen species (ROS)-responsive micelles (RT-NM) loading rapamycin or gypenoside XVII. Guided by RP-1 peptide, the ligand of receptor for advanced glycation end products (RAGE), RT-NM efficiently targeted neurons and microglia in AD-affected region. This nano-combination therapy activated the whole autophagy-lysosome pathway by autophagy induction (rapamycin) and lysosome improvement (gypenoside XVII), thus enhancing autophagic degradation of neurotoxic aggregates and inflammasomes, and promoting A
Erdafitinib in BCG-treated high-risk non-muscle-invasive bladder cancer
Authors: J.W.F. Catto, B. Tran, M. Rouprêt, J.E. Gschwend, Y. Loriot, H. Nishiyama, J.P. Redorta, S. Daneshmand, S.A. Hussain, H.J. Cutuli, G. Procopio, V. Guadalupi, N. Vasdev, V. Naini, L. Crow, S. Triantos, M. Baig, G. Steinberg, Ruben Bengio, Hernan Cutuli, Jorge Salinas, Filip Ameye, Steven Joniau, Diogo Rodrigues da Rosa, Karine Martins da Trindade, Murilo Almeida Luz, Mario Henrique Bavaresco, Adriano de Paula, Jose Santiag, Shaogang Wang, Dingwei Ye, Martin Boegemann, Florian Roghmann, Albert Heidrich, Eva Hellmis, Óscar Rodriguez Faba, Jose Luis Dominguez, Romain Mathieu, Marc Colombel, Franck Bladou, Xavier Artignan, Nikhil Vasdev, Rajendra Shimpi, Valentina Guadalupi, Rosa Tambaro, Zuzana Sirotova, Massimiliano Spada, Andrea Necchi, Hiroomi Nakatsu, Eiji Kikuchi, Nobuaki Shimizu, Kent Kanao, Makoto Sumitomo, Yushi Naito, Won Sik Ham, Seung-Il Jung, Hongkoo Ha, Kwan Joong Joo, Ja Hyeon Ku, Ho Kyung Seo, Seokjoong Yun, Anna Kolodziej, Janusz Lawinski, David Morris, Siamak Daneshmand, Badar Mian, Eugene Lee
Journal: Annals of Oncology (2023)

Treatment options are limited for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) with disease recurrence after bacillus Calmette-Guérin (BCG) treatment and who are ineligible for/refuse radical cystectomy. FGFR alterations are commonly detected in NMIBC. We evaluated the activity of oral erdafitinib, a selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, versus intravesical chemotherapy in patients with high-risk NMIBC and select FGFR3/2 alterations following recurrence after BCG treatment.
Erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select FGFR alterations: cohort 2 of the randomized phase III THOR trial
Authors: A.O. Siefker-Radtke, N. Matsubara, S.H. Park, R.A. Huddart, E.F. Burgess, M. Özgüroğlu, B.P. Valderrama, B. Laguerre, U. Basso, S. Triantos, S. Akapame, Y. Kean, K. Deprince, S. Mukhopadhyay, Y. Loriot, Patricia Bastick, Sanjeev Sewak, Ben Tran, Martin Pichler, Shahrokh Shariat, Sylvie Rottey, Peter Schatteman, Dirk Schrijvers, Vincent Verschaeve, Christof Vulsteke, Luiza Aleixo Barros Leite Ferreira, Pereira de Santana Gomes Andrea Juliana, Joao Antonio Junior, Sergio Azevedo, Diogo Bastos, Giuliano Borges, Aldo Dettino, Pires Luis Antonio, Murilo Luz, Suelen Martins, Jose Mauricio Mota, Joseane Toledo, Bernhard Eigl, Daygen Finch, Joel Gingerich, Haiying Dong, Jian Huang, Jie Jin, Hongming Pan, Zhongquan Sun, Ye Tian, Ben Wan, Bin Wu, Ting Xu, Wei Xue, Fangjian Zhou, Philippe Barthelemy, Delphine Borchiellini, Fabien Calcagno, Aurelien Carnot, Pierre Cornillon, Remy Delva, Sheik Emambux, Nadine Houede, Brigitte Laguerre, Géraldine Lauridant, Yohann Loriot, Hakim Mahammedi, Denis Maillet, Damien Pouessel, Guilhem Roubaud, Friederike Schlurmann-Constans, Diego Tosi, Sylvie Zanetta, Severine Banek, Susan Feyerabend, Mario Kramer, Guenther Niegisch, Philipp Nuhn, Marco Schnabel, Christian Wuelfing, Sofia Baka, Aristotelis Bamias, George Fountzilas, Harabolos Kalofonos, Konstantinos Karalis, Athanasios Kotsakis, Eleni Timotheadou, Laszlo Landherr, Laszlo Mangel, Avivit Pe’er, Meital Levratovsky, Umberto Basso, Nicola Battelli, Alessia Cavo, Ugo De Giorgi, Laura Doni, Luca Galli, Maria Olga Gigante, Valentina Guadalupi, Michele Maio, Laura Milesi, Franco Nolè, Giorgio Scagliotti, Giampaolo Tortora, Satoshi Fukasawa, Toru Harabayashi, Naoto Kamiya, Takashi Kawahara, Mutsushi Kawakita, Nobunaki Matsubara, Kazumasa Matsumoto, Kazuo Nishimura, Taoka Rikiya, Nobuaki Shimizu, Toshio Tagaki, Taek Won Kang, Jwa Hoon Kim, SeHyun Kim, Hyo Jin Lee, Yun-Gyoo Lee, Sun Young Rha, Ho Kyung Seo, Maartje Los, Bogdan Zurawski, Paulo Cortes, Catia Faustino, Nuno Sineiro Vau, Ricardo da Luz, Vagif Atduev, Dmitry Kirtbaya, Evgeny Kopyltsov, Aleksandr Lykov, Urmantsev Marat, Sergey Orlov, Konstantin Penkov, Albert Pirmagomedov, Andrey Semenov, Sergey Varlamov, Georgia Anguera, Montserrat Domenech, Regina Girones, Aranzazu Gonzalez del Alba, Nuria Lainez Milagro, Raquel Luque, Esther Martínez Ortega, Begoña Mellado, María Jose Méndez Vidal, Esteban Nogales Fernandez, Begoña Perez Valderrama, Alvaro Pinto Marín, Carmen Santander, Yi-Hsiu Huang, Wen-Pin Su, Hung-Chan Wu, WenJeng Wu, Kai-Jie Yu, Ahmet Bilici, Erdem Goker, Mahmut Gumus, Aziz Karaoglu, Umut Kefeli, Fatih Köse, Mustafa Ozguroglu, Deniz Tural, Haci Turk, Suayib Yalcin, Igor Bondarenko, Gennadii Khareba, Yana Kidik, Oleksandr Lychkovskyy, Valerii Sakalo, Serghii Shevnia, Eduard Stakhovskyy, Amit Bahl, Simon Crabb, Thomas Powles, Peter Sankey, Mohammad Sarwar, Pasquale Benedetto, Earle Burgess, Nancy Dawson, Gurjyot Doshi, Mark Fleming, Joseph Maly, Mamta Parikh, David Waterhouse
Journal: Annals of Oncology (2023)
WITHDRAWN: Efficacy of Oral SERDs in the treatment of ER+, HER2 - metastatic breast cancer, a stratified analysis of the ESR1 wild type and mutant subgroups
Authors: N.Z.H. Wong, D.W.T. Yap, R.J.M. Ong, J.J. Zhao, Y.H. Chan, J.C.S. Tey, R. Sundar, J.S.J. Lim, S.S. Dawood
Journal: Annals of Oncology (2023)

Oral SERDs are a novel drug class that have been developed to counteract resistance due to ESR1 mutations. Several SERDs have emerged from phase 2 and 3 trials, with the FDA limiting approval for Elacestrant to patients with ESR1mt tumours despite PFS benefit in the overall population. However, questions remain on whether patients with ESR1wt tumours stand to benefit from oral SERDs.Manuscripts and conference presentations of Randomised Controlled Trials were extracted after a systematic search of Embase, PubMed and Cochrane from inception until January 21,2023. RCTs investigating the efficacy of oral SERDs versus endocrine therapy for ER positive, HER2 negative advanced breast cancer, and which reported the Kaplan Meier (KM) curves of PFS in the overall and ESR1 mutant (ESR1mt) population were selected. A graphical reconstructive algorithm was applied to estimate time-to-event outcomes from reported KM curves in all overall and ESR1mt cohorts. A bipartite matching algorithm, KMSubtraction, was used to derive survival data for unreported (ESR1wt) subgroups. An individual patient data (IPD) meta-analysis was then pursued, pooling data by ESR1 mutation status in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Cochrane Guidelines for IPD.The randomized clinical trials ACELERA, AMEERA-3, EMERALD and SERENA-2 were included, totalling 1290 patients. In the pooled analysis of the overall cohort, PFS benefit was observed with oral SERDs when compared with treatment of physicians choice (TPC) (HR 0.783, 95%CI 0.681-0.900, p<0.001). In the ESR1mt subgroup, oral SERDs demonstrated improved PFS (HR 0.557, 95%CI 0.440-0.705, p<0.001) compared to TPC. In the ESR1wt subgroup, oral SERDs demonstrated no significant PFS benefit (HR 0.944, 95%CI 0.783-1.138, p=0.543) when compared to TPC.The results of this IPD meta-analysis suggests that PFS benefit in the overall population is mainly driven by the ESR1mt subgroup.
CXCR2 chemokine receptor – a master regulator in cancer and physiology
Authors: Gwendal Lazennec, Krishna Rajarathnam, Ann Richmond
Journal: Trends in Molecular Medicine (2023)

Recent findings have modified our understanding of the roles of chemokine receptor CXCR2 and its ligands in cancer, inflammation, and immunity. Studies in Cxcr2 tissue-specific knockout mice show that this receptor is involved in, among other things, cancer, central nervous system (CNS) function, metabolism, reproduction, COVID-19, and the response to circadian cycles. Moreover, CXCR2 involvement in neutrophil function has been revisited not only in physiology but also for its major contribution to cancers. The recent unfolding of the role of CXCR2 in numerous cancers has led to extensive evaluation of multiple CXCR2 antagonists in preclinical and clinical studies. In this review we discuss the potential of targeting CXCR2 for cancer treatment.
Phase II study of durvalumab and tremelimumab with front-line neoadjuvant chemotherapy in patients with advanced-stage ovarian cancer: primary analysis in the original cohort of KGOG3046/TRU-D
Authors: Junsik Park, Jung Bok Lee, Myong Cheol Lim, Byoung-Gie Kim, Jae-Weon Kim, Sunghoon Kim, Chel Hun Choi, Hee Seung Kim, Sang Yoon Park, Jung-Yun Lee
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background This study assessed the antitumor activity and safety of durvalumab plus tremelimumab combined with neoadjuvant chemotherapy (NAC) in patients newly diagnosed with advanced ovarian cancer. Here, we report the primary endpoint of the original cohort of the KGOG 3046/TRU-D study. Methods In this investigator-initiated single-arm, phase II trial, patients with stage IIIC-IVB ovarian cancer were administered three cycles of durvalumab (1500 mg) and tremelimumab (75 mg) with NAC, followed by interval debulking surgery (IDS). After surgery, three cycles of durvalumab (1120 mg) and adjuvant chemotherapy followed by durvalumab maintenance (1120 mg [total 12 cycles]) were administered. The primary endpoint of the study was 12-month progression-free survival (PFS) rate. Results Twenty-three patients were enrolled. The median patient age was 60 years (range 44–77 years), and most patients presented with high-grade serous carcinoma (87.0%) and stage IV disease (87.0%). At the time of data cut-off on January 17, 2023, the median follow-up duration was 29.2 months (range 12.0–42.2). The 12-month, 24-month, and 30 month PFS rates were 63.6%, 45.0%, and 40.0%, respectively. All patients underwent IDS, with an R0 resection rate of 73.9%, and 17.4% achieved pathological complete response. Skin rashes were the most common treatment-related adverse events (TRAEs, 69.6%). However, all TRAEs completely resolved after steroid use. Conclusion This study showed promising activity with a durable clinical response, supporting the potential of NAC with dual immune checkpoint blockade in advanced-stage ovarian cancer. Trial registration number NCT03899610 .
Pretreatment radiomic biomarker for immunotherapy responder prediction in stage IB–IV NSCLC (LCDigital-IO Study): a multicenter retrospective study
Authors: Shaowei Wu, Weijie Zhan, Lan Liu, Daipeng Xie, Lintong Yao, Henian Yao, Guoqing Liao, Luyu Huang, Yubo Zhou, Peimeng You, Zekai Huang, Qiaxuan Li, Bin Xu, Siyun Wang, Guangyi Wang, Dong-Kun Zhang, Guibin Qiao, Lawrence Wing-Chi Chan, Michael Lanuti, Haiyu Zhou
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background The predictive efficacy of current biomarker of immune checkpoint inhibitors (ICIs) is not sufficient. This study investigated the causality between radiomic biomarkers and immunotherapy response status in patients with stage IB–IV non-small cell lung cancer (NSCLC), including its biological context for ICIs treatment response prediction. Methods CT images from 319 patients with pretreatment NSCLC receiving immunotherapy between January 2015 and November 2021 were retrospectively collected and composed a discovery (n=214), independent validation (n=54), and external test cohort (n=51). A set of 851 features was extracted from tumorous and peritumoral volumes of interest (VOIs). The reference standard is the durable clinical benefit (DCB, sustained disease control for more than 6 months assessed via radiological evaluation). The predictive value of combined radiomic signature (CRS) for pathological response was subsequently assessed in another cohort of 98 patients with resectable NSCLC receiving ICIs preoperatively. The association between radiomic features and tumor immune landscape on the online data set (n=60) was also examined. A model combining clinical predictor and radiomic signatures was constructed to improve performance further. Results CRS discriminated DCB and non-DCB patients well in the training and validation cohorts with an area under the curve (AUC) of 0.82, 95% CI: 0.75 to 0.88, and 0.75, 95% CI: 0.64 to 0.87, respectively. In this study, the predictive value of CRS was better than programmed cell death ligand-1 (PD-L1) expression (AUC of PD-L1 subset: 0.59, 95% CI: 0.50 to 0.69) or clinical model (AUC: 0.66, 95% CI: 0.51 to 0.81). After combining the clinical signature with CRS, the predictive performance improved further with an AUC of 0.837, 0.790 and 0.781 in training, validation and D2 cohorts, respectively. When predicting pathological response, CRS divided patients into a major pathological response (MPR) and non-MPR group (AUC: 0.76, 95% CI: 0.67 to 0.81). Moreover, CRS showed a promising stratification ability on overall survival (HR: 0.49, 95% CI: 0.27 to 0.89; p=0.020) and progression-free survival (HR: 0.43, 95% CI: 0.26 to 0.74; p=0.002). Conclusion By analyzing both tumorous and peritumoral regions of CT images in a radiomic strategy, we developed a non-invasive biomarker for distinguishing responders of ICIs therapy and stratifying their survival outcome efficiently, which may support the clinical decisions on the use of ICIs in advanced as well as patients with resectable NSCLC.